Abstract The proposed research aims to measure blood oxygenation level dependent (BOLD) signals in white matter (WM) using functional magnetic resonance imaging (fMRI), validate their relationships to cortical neural activity, and quantify their characteristics and their underlying biophysical origins. BOLD signals have previously been robustly detected in gray matter (GM) in response to stimuli in a very large number of studies. In addition, correlations of signal fluctuations between cortical regions in a resting state have been analyzed to derive functional connectivity. However, whether such signals reliably arise in WM remains controversial, and their interpretation is unclear. We have previously shown that BOLD signals can be reliably detected in WM if appropriate detection and analysis methods are used, and that in a resting state they exhibit anisotropic temporal correlations that largely align with WM tracts. Multiple such lines of evidence converge to suggest that WM BOLD signals are related to intrinsic, function-dependent neural activity and are apparent only in tracts engaged in specific functions. However, the precise relationships between WM and corresponding GM signals have not been established, and neither the characteristics nor origins of the hemodynamic response function (HRF) of WM have been elucidated. We hypothesize that BOLD signal variations in WM tracts are directly related to corresponding variations in neural activity in GM volumes to which they connect and/or which share specific functional roles, and that further studies will provide a new basis for more fully integrating structural and functional aspects of neural organization. In the proposed research we will [1] demonstrate and measure the relationships between BOLD signals in WM tracts (identified using diffusion imaging) and GM volumes in response to parametric stimuli whose variations modulate the degree of neural activity in specific cortical areas; [2] measure and characterize the HRF in specific WM tracts using event-related fMRI, and modify conventional models of BOLD responses to explain and fit those data; [3] establish the biophysical basis of stimulus-evoked BOLD activations in white matter by comparing data from different imaging sequences and field strengths, and by measuring BOLD signals in the brains of non-human primates with and without an intravascular susceptibility contrast agent to separate contributions from changes in blood volume vs blood oxygenation. Overall, these studies will validate the nature of WM BOLD effects, demonstrate their relevance in neural processing, and provide a basis for future studies of functional changes in a broad range of WM- associated disorders as well as development and degeneration.